Rare Copy Number Variants Research Articles

Contribution of common and rare variants to bipolar disorder susceptibility in extended pedigrees from population isolates

Current evidence from case/control studies indicates that genetic risk for psychiatric disorders derives primarily from numerous common variants, each with a small phenotypic impact. The literature describing apparent segregation of bipolar disorder (BP) in numerous multigenerational pedigrees suggests that, in such families, large-effect inherited variants might play a greater role. To identify roles of rare and common variants on BP, we conducted genetic analyses in 26 Colombia and Costa Rica pedigrees ascertained for bipolar disorder 1 (BP1), the most severe and heritable form of BP. In these pedigrees, we performed microarray SNP genotyping of 838 individuals and high-coverage whole-genome sequencing of 449 individuals. We compared polygenic risk scores (PRS), estimated using the latest BP1 genome-wide association study (GWAS) summary statistics, between BP1 individuals and related controls. We also evaluated whether BP1 individuals had a higher burden of rare deleterious single-nucleotide variants (SNVs) and rare copy number variants (CNVs) in a set of genes related to BP1. We found that compared with unaffected relatives, BP1 individuals had higher PRS estimated from BP1 GWAS statistics (P = 0.001 ~ 0.007) and displayed modest increase in burdens of rare deleterious SNVs (P = 0.047) and rare CNVs (P = 0.002 ~ 0.033) in genes related to BP1. We did not observe rare variants segregating in the pedigrees. These results suggest that small-to-moderate effect rare and common variants are more likely to contribute to BP1 risk in these extended pedigrees than a few large-effect rare variants.

Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component whose knowledge evolves quickly. Next-generation sequencing is the only effective technology to deal with the high genetic heterogeneity of ASD in a clinical setting. However, rigorous criteria to classify rare genetic variants conferring ASD susceptibility are currently lacking. We have performed whole-exome sequencing to identify both nucleotide variants and copy number variants (CNVs) in 253 ASD patients, including 68 patients with intellectual disability (ID) and 90 diagnosed as Asperger syndrome. Using explicit criteria to classify both susceptibility genes and susceptibility variants we prioritized 217 genes belonging to the following categories: syndromic genes, genes with an excess of de novo protein truncating variants and genes targeted by rare CNVs. We obtained a susceptibility variant detection rate of 19.7% (95% CI: [15–25.2%]). The rate for CNVs was 7.1% (95% CI: [4.3–11%]) and 12.6% (95% CI: [8.8–17.4%]) for nucleotide variants. The highest rate (30.1%, 95% CI: [20.2–43.2%]) was obtained in the ASD + ID subgroup. A strong contributor for at risk nucleotide variants was the recently identified set of genes (n = 81) harboring an excess of de novo protein truncating variants. Since there is currently no evidence that the genes targeted here are necessary and sufficient to cause ASD, we recommend to avoid the term “causative of ASD” when delivering the information about a variant to a family and to use instead the term “genetic susceptibility factor contributing to ASD”.

An integrated analysis of rare CNV and exome variation in Autism Spectrum Disorder using the Infinium PsychArray.

Autism spectrum disorder (ASD) is a neurodevelopmental condition with a complex and heterogeneous genetic etiology. While a proportion of ASD risk is attributable to common variants, rare copy-number variants (CNVs) and protein-disrupting single-nucleotide variants (SNVs) have been shown to significantly contribute to ASD etiology. We analyzed a homogeneous cohort of 127 ASD Italian families genotyped with the Illumina PsychArray, to perform an integrated analysis of CNVs and SNVs and to assess their contribution to ASD risk. We observed a higher burden of rare CNVs, especially deletions, in ASD individuals versus unaffected controls. Furthermore, we identified a significant enrichment of rare CNVs intersecting ASD candidate genes reported in the SFARI database. Family-based analysis of rare SNVs genotyped by the PsychArray also indicated an increased transmission of rare SNV variants from heterozygous parents to probands, supporting a multigenic model of ASD risk with significant contributions of both variant types. Moreover, our study reinforced the evidence for a significant role of VPS13B, WWOX, CNTNAP2, RBFOX1, MACROD2, APBA2, PARK2, GPHN, and RNF113A genes in ASD susceptibility. Finally, we showed that the PsychArray, besides providing useful genotyping data in psychiatric disorders, is a valuable and cost-efficient tool for genic CNV detection, down to 10 kb.

A highly sensitive and specific workflow for detecting rare copy-number variants from exome sequencing data

BackgroundExome sequencing (ES) is a first-tier diagnostic test for many suspected Mendelian disorders. While it is routine to detect small sequence variants, it is not a standard practice in clinical settings to detect germline copy-number variants (CNVs) from ES data due to several reasons relating to performance. In this work, we comprehensively characterized one of the most sensitive ES-based CNV tools, ExomeDepth, against SNP array, a standard of care test in clinical settings to detect genome-wide CNVs.MethodsWe propose a modified ExomeDepth workflow by excluding exons with low mappability prior to variant calling to drastically reduce the false positives originating from the repetitive regions of the genome, and an iterative variant calling framework to assess the reproducibility. We used a cohort of 307 individuals with clinical ES data and clinical SNP array to estimate the sensitivity and false discovery rate of the CNV detection using exome sequencing. Further, we performed targeted testing of the STRC gene in 1972 individuals. To reduce the number of variants for downstream analysis, we performed a large-scale iterative variant calling process with random control cohorts to assess the reproducibility of the CNVs.ResultsThe modified workflow presented in this paper reduced the number of total variants identified by one third while retaining a higher sensitivity of 97% and resulted in an improved false discovery rate of 11.4% compared to the default ExomeDepth pipeline. The exclusion of exons with low mappability removes 4.5% of the exons, including a subset of exons (0.6%) in disease-associated genes which are intractable by short-read next-generation sequencing (NGS). Results from the reproducibility analysis showed that the clinically reported variants were reproducible 100% of the time and that the modified workflow can be used to rank variants from high to low confidence. Targeted testing of 30 CNVs identified in STRC, a challenging gene to ascertain by NGS, showed a 100% validation rate.ConclusionsIn summary, we introduced a modification to the default ExomeDepth workflow to reduce the false positives originating from the repetitive regions of the genome, created a large-scale iterative variant calling framework for reproducibility, and provided recommendations for implementation in clinical settings.

Rapid, Paralog-Sensitive CNV Analysis of 2457 Human Genomes Using QuicK-mer2.

Gene duplication is a major mechanism for the evolution of gene novelty, and copy-number variation makes a major contribution to inter-individual genetic diversity. However, most approaches for studying copy-number variation rely upon uniquely mapping reads to a genome reference and are unable to distinguish among duplicated sequences. Specialized approaches to interrogate specific paralogs are comparatively slow and have a high degree of computational complexity, limiting their effective application to emerging population-scale data sets. We present QuicK-mer2, a self-contained, mapping-free approach that enables the rapid construction of paralog-specific copy-number maps from short-read sequence data. This approach is based on the tabulation of unique k-mer sequences from short-read data sets, and is able to analyze a 20X coverage human genome in approximately 20 min. We applied our approach to newly released sequence data from the 1000 Genomes Project, constructed paralog-specific copy-number maps from 2457 unrelated individuals, and uncovered copy-number variation of paralogous genes. We identify nine genes where none of the analyzed samples have a copy number of two, 92 genes where the majority of samples have a copy number other than two, and describe rare copy number variation effecting multiple genes at the APOBEC3 locus.

Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations

Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10−3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.

The genetics of bipolar disorder.

Bipolar disorder (BD) is one of the most heritable mental illnesses, but the elucidation of its genetic basis has proven to be a very challenging endeavor. Genome-Wide Association Studies (GWAS) have transformed our understanding of BD, providing the first reproducible evidence of specific genetic markers and a highly polygenic architecture that overlaps with that of schizophrenia, major depression, and other disorders. Individual GWAS markers appear to confer little risk, but common variants together account for about 25% of the heritability of BD. A few higher-risk associations have also been identified, such as a rare copy number variant on chromosome 16p11.2. Large scale next-generation sequencing studies are actively searching for other alleles that confer substantial risk. As our understanding of the genetics of BD improves, there is growing optimism that some clear biological pathways will emerge, providing a basis for future studies aimed at molecular diagnosis and novel therapeutics.

Investigating Genetic Factors Contributing to Variable Expressivity of Class I 17p13.3 Microduplication.

17p13.3 microduplications are rare copy number variations (CNVs) associated with variable phenotypes, including facial dysmorphism, developmental delay, intellectual disability, and autism. Typically, when a recognized pathogenic CNV is identified, other genetic factors are not considered. We investigated via whole-exome sequencing the presence of additional variants in four carriers of class I 17p13.3 microduplications. A 730 kb 17p13.3 microduplication was identified in two half-brothers with intellectual disability, but not in a third affected half-brother or blood cells from their normal mother (Family A), thus leading to the hypothesis of maternal germline mosaicism. No additional pathogenic variants were detected in Family A. Two affected siblings carried maternally inherited 450 kb 17p13.3 microduplication (Family B); the three carriers of the microduplication exhibited microcephaly and learning disability/speech impairment of variable degrees. Exome analysis revealed a variant of uncertain significance in RORA, a gene already linked to autism, in the autistic boy; his sister was heterozygous for a CYP1B1 pathogenic variant that could be related to her congenital glaucoma. Besides, both siblings carried a loss-of-function variant in DIP2B, a candidate gene for intellectual disability, which was inherited from their father, who also exhibited learning disability in childhood. In conclusion, additional pathogenic variants were revealed in two affected carriers of class I 17p13.3 microduplication (Family B), probably adding to their phenotypes. These results provided new evidence regarding the contribution of RORA and DIP2B to neurocognitive deficits, and highlighted the importance of full genetic investigation in carriers of CNV syndromes with variable expressivity. Finally, we suggest that microcephaly may be a rare clinical feature also related to the presence of the class I 17p13.3 microduplication.

Influence of De novo mutation in autism

Autism and autism spectrum disorders (ASD) affects the areas of social awareness and interaction, verbal and nonverbal communication, and behaviors and interests, which are grouped among neurobehavioral disorders. One in 68 children is affected with ASD according to the estimate from the Center for Disease Control and Prevention's autism and developmental disabilities monitoring network and an increasing prevalence observed worldwide. A characteristic heterogeneity in ASD determined genetic variability as a major contributor. Whole-exome sequencing of ASD individuals revealed that discrete de novo mutation (single-nucleotide variation or small indels) also contribute to the overall genetic risk of ASD apart from rare genetic variation affecting single nucleotides of protein-coding DNA or rare genomic copy number variants as assessed through other high-throughput genomic methods. These genes are involved in synaptic transmission and regulated during brain development by acting upstream or downstream of Wingless- related integration site (WNT), bone morphogenetic proteins/transforming growth factor-β, sonic hedgehog, fibroblast growth factor, and retinoic acid signaling pathways. The current review focuses on genes involved in synaptic function, undergoing de novo mutation leading to ASD condition.

Beyond the coding genome: non-coding mutations and cancer.

Latest advancements in genomics involving individuals from different races and geographical locations has led to the identification of thousands of common as well as rare genetic variants and copy number variations (CNVs). These studies have surprisingly revealed that the majority of genetic variation is not present within the coding region but rather in the non-coding region of the genome, which is also termed as "Medical Genome". This short review describes how mutations/variations within; regulatory sequences, architectural proteins and transcriptional regulators give rise to the aberrant gene expression profiles that drives cellular transformations and malignancies.

High-resolution chromosomal microarrayanalysis for copy-number variations in high-functioning autism reveals large aberration typical for intellectual disability.

Copy-number variants (CNVs), in particular rare, small and large ones (< 1% frequency) and those encompassing brain-related genes, have been shown to be associated with neurodevelopmental disorders like autism spectrum disorders (ASDs), attention deficit hyperactivity disorder (ADHD), and intellectual disability (ID). However, the vast majority of CNV findings lack specificity with respect to autistic or developmental-delay phenotypes. Therefore, the aim of the study was to investigate the size and frequency of CNVs in high-functioning ASD (HFA) without ID compared with a random population sample and with published findings in ASD and ID. To investigate the role of CNVs for the "core symptoms" of high-functioning autism, we included in the present exploratory study only patients with HFA without ID. The aim was to test whether HFA have similar large rare (> 1Mb) CNVs as reported in ASD and ID. We performed high-resolution chromosomal microarray analysis in 108 children and adolescents with HFA without ID. There was no significant difference in the overall number of rare CNVs compared to 124 random population samples. However, patients with HFA carried significantly more frequently CNVs containing brain-related genes. Surprisingly, six HFA patients carried very large CNVs known to be typically present in ID. Our findings provide new evidence that not only small, but also large CNVs affecting several key genes contribute to the genetic etiology/risk of HFA without affecting their intellectual ability.

Predictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically.

Copy number variation profiling in pharmacogenes using panel-based exome resequencing and correlation to human liver expression.

Structural variants including copy number variations (CNV) have gained widespread attention, especially in pharmacogenomics but for several genes functional relevance and clinical evidence are still lacking. Detection of CNVs in next-generation sequencing data is challenging but offers widespread applications. We developed a cohort-based CNV detection workflow to extract CNVs from read counts of targeted NGS of 340 genes involved in absorption, distribution, metabolism and excretion (ADME) of drugs. We applied our method to 150 human liver tissue samples and correlated identified CNVs to mRNA expression levels. In total, we identified 445 deletions (73%) and 167 duplications (27%) in 36 pharmacogenes including all well-known CNVs of CYPs, GSTs, SULTs, UGTs, numerous described rare CNVs of CYP2E1, SLC16A3 or UGT2B15 as well as novel observations, e.g., for SLC22A12, SLC22A17 and GPS2 (G Protein Pathway Suppressor 2). We were able to fine-map complex CNVs of CYP2A6 and CYP2D6 with exon resolution. Correlation analysis confirmed known expression patterns for common CNVs and suggested an influence on expression variability for some rare CNVs. Our straightforward CNV detection workflow can be easily applied to any NGS coverage data and helped to analyze CNVs in an ADME-NGS panel of 340 pharmacogenes to improve genotype-phenotype correlations.

Copy Number Variations in a Cohort of 420 Individuals with Neurodevelopmental Disorders From the South of Brazil

Chromosomal microarray (CMA) is now recommended as first tier for the evaluation in individuals with unexplained neurodevelopmental disorders (ND). However, in developing countries such as Brazil, classical cytogenetic tests are still the most used in clinical practice, as reflected by the scarcity of publications of microarray investigation in larger cohorts. This is a retrospective study which analyses the reading files of CMA and available clinical data from 420 patients from the south of Brazil, mostly children, with neurodevelopmental disorders requested by medical geneticists and neurologists for diagnostic purpose. Previous karyotyping was reported for 138 and includes 17 with abnormal results. The platforms used for CMA were CYTOSCAN 750K (75%) and CYTOSCAN HD (25%). The sex ratio of the patients was 1.625 males :1 female and the mean age was 9.5 years. A total of 96 pathogenic copy number variations (CNVs), 58 deletions and 38 duplications, were found in 18% of the patients and in all chromosomes, except chromosome 11. For 12% of the patients only variants of uncertain clinical significance were found. No clinically relevant CNV was found in 70%. The main referrals for chromosomal microarrays (CMA) were developmental delay (DD), intellectual disability (ID), facial dysmorphism and autism spectrum disorder (ASD). DD/ID were present in 80%, facial dysmorphism in 52% and ASD in 32%. Some phenotypes in this population could be predictive of a higher probability to carry a pathogenic CNV, as follows: dysmorphic facial features (p-value = < 0.0001, OR = 0.32), obesity (p-value = 0.006, OR = 0.20), short stature (p-value = 0.032, OR = 0.44), genitourinary anomalies (p-value = 0.032, OR = 0.63) and ASD (p-value = 0.039, OR = 1.94). The diagnostic rate for CMA in this study was 18%. We present the largest report of CMA data in a cohort with ND in Brazil. We characterize the rare CNVs found together with the main phenotypes presented by each patient, list phenotypes which could predict a higher diagnostic probability by CMA in patients with a neurodevelopmental disorder and show how CMA and classical karyotyping results are complementary.

Rare copy number variants in individuals at clinical high risk for psychosis: Enrichment of synaptic/brain-related functional pathways.

Schizophrenia is a complex and chronic neuropsychiatric disorder, with a heritability of around 60-80%. Large (>100 kb) rare (<1%) copy number variants (CNVs) occur more frequently in schizophrenia patients compared to controls. Currently, there are no studies reporting genome-wide CNVs in clinical high risk for psychosis (CHR-P) individuals. The aim of this study was to investigate the role of rare genome-wide CNVs in 84 CHR-P individuals and 124 presumably healthy controls. There were no significant differences in all rare CNV frequencies and sizes between CHR-P individuals and controls. However, brain-related CNVs and brain-related deletions were significantly more frequent in CHR-P individuals than controls. In CHR-P individuals, significant associations were found between brain-related CNV carriers and attenuated positive symptoms syndrome or cognitive disturbances (OR = 3.07, p = .0286). Brain-related CNV carriers experienced significantly higher negative symptoms (p = .0047), higher depressive symptoms (p = .0175), and higher disturbances of self and surroundings (p = .0029) than noncarriers. Furthermore, enrichment analysis of genes was performed in the regions of rare CNVs using three independent methods, which confirmed significant clustering of predefined genes involved in synaptic/brain-related functional pathways in CHR-P individuals. These results suggest that rare CNVs might affect synaptic/brain-related functional pathways in CHR-P individuals.

Increased schizophrenia family history burden and reduced premorbid IQ in treatment-resistant schizophrenia: a Swedish National Register and Genomic Study.

A high proportion of those with schizophrenia experience treatment non-response, placing them at higher risk for mortality and suicide attempts, compared to treatment responders. The clinical, social, and economic burden of treatment-resistant schizophrenia (TRS) are substantial. Previous genomic and epidemiological studies of TRS were often limited by sample size or lack of comprehensive genomic data. We aimed to systematically understand the clinical, demographic, and genomic correlates of TRS using epidemiological and genetic epidemiological modelling in a Swedish national population sample (n = 24,706) and then in a subgroup with common variant genetic risk scores, rare copy-number variant burden, and rare exonic burden (n = 4936). Population-based analyses identified increasing schizophrenia family history to be significantly associated with TRS (highest quartile of familial burden vs. lowest: adjusted odds ratio (aOR): 1.31, P = 4.8 × 10-8). In males, a decrease of premorbid IQ of one standard deviation was significantly associated with greater risk of TRS (minimal aOR: 0.94, P = 0.002). In a subset of cases with extensive genomic data, we found no significant association between the genetic risk scores of four psychiatric disorders and two cognitive traits with TRS (schizophrenia genetic risk score: aOR = 1.07, P = 0.067). The association between copy number variant and rare variant burden measures and TRS did not reach the pre-defined statistical significance threshold (all P ≥ 0.005). In conclusion, direct measures of genomic risk were not associated with TRS; however, premorbid IQ in males and schizophrenia family history were significantly correlated with TRS and points to new insights into the architecture of TRS.

Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.

Large genomic databases of neurodevelopmental disorders (NDD) are helpful resources of genomic variations in complex and heterogeneous conditions, as Autism Spectrum Disorder (ASD). We evaluated the role of rare copy number variations (CNVs) and exonic de novo variants, in a molecularly unexplored Brazilian cohort of 30 ASD trios (n = 90), by performing a meta-analysis of our findings in more than 20,000 patients from NDD cohorts. We identified three pathogenic CNVs: two duplications on 1q21 and 17p13, and one deletion on 4q35. CNVs meta-analysis (n = 8,688 cases and n = 3,591 controls) confirmed 1q21 relevance by identifying duplications in other 16 ASD patients. Exome analysis led the identification of seven de novo variants in ASD genes (SFARI list): three loss-of-function pathogenic variants in CUL3, CACNA1H, and SHANK3; one missense pathogenic variant in KCNB1; and three deleterious missense variants in ATP10A, ANKS1B, and DOCK1. From the remaining 12 de novo variants in non-previous ASD genes, we prioritized PRPF8 and RBM14. Meta-analysis (n = 13,754 probands; n = 2,299 controls) identified six and two additional patients with validated de novo variants in PRPF8 and RBM14, respectively. By comparing the de novo variants with a previously established mutational rate model, PRPF8 showed nominal significance before multiple test correction (P = 0.039, P-value adjusted = 0.079, binomial test), suggesting its relevance to ASD. Approximately 60% of our patients presented comorbidities, and the diagnostic yield was estimated in 23% (7/30: three pathogenic CNVs and four pathogenic de novo variants). Our uncharacterized Brazilian cohort with tetra-hybrid ethnic composition was a valuable resource to validate and identify possible novel candidate loci. Autism Res 2020, 13: 199-206. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We believed that to study an unexplored autistic population, such as the Brazilian, could help to find novel genes for autism. In order to test this idea, with our limited budget, we compared candidate genes obtained from genomic analyses of 30 children and their parents, with those of more than 20,000 individuals from international studies. Happily, we identified a genetic cause in 23% of our patients and suggest a possible novel candidate gene for autism (PRPF8).

Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia

Severe hypertriglyceridemia (HTG) is a relatively common form of dyslipidemia with a complex pathophysiology and serious health complications. HTG can develop in the presence of rare genetic factors disrupting genes involved in the triglyceride (TG) metabolic pathway, including large-scale copy-number variants (CNVs). Improvements in next-generation sequencing technologies and bioinformatic analyses have better allowed assessment of CNVs as possible causes of or contributors to severe HTG. We screened targeted sequencing data of 632 patients with severe HTG and identified partial deletions of the LPL gene, encoding the central enzyme involved in the metabolism of TG-rich lipoproteins, in four individuals (0.63%). We confirmed the genomic breakpoints in each patient with Sanger sequencing. Three patients carried an identical heterozygous deletion spanning the 5' untranslated region (UTR) to LPL exon 2, and one patient carried a heterozygous deletion spanning the 5'UTR to LPL exon 1. All four heterozygous CNV carriers were determined to have multifactorial severe HTG. The predicted null nature of our identified LPL deletions may contribute to relatively higher TG levels and a more severe clinical phenotype than other forms of genetic variation associated with the disease, particularly in the polygenic state. The identification of novel CNVs in patients with severe HTG suggests that methods for CNV detection should be included in the diagnostic workup and molecular genetic evaluation of patients with high TG levels.

Attention-deficit hyperactivity disorder shares copy number variant risk with schizophrenia and autism spectrum disorder

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable common childhood-onset neurodevelopmental disorder. Some rare copy number variations (CNVs) affect multiple neurodevelopmental disorders such as intellectual disability, autism spectrum disorders (ASD), schizophrenia and ADHD. The aim of this study is to determine to what extent ADHD shares high risk CNV alleles with schizophrenia and ASD. We compiled 19 neuropsychiatric CNVs and test 14, with sufficient power, for association with ADHD in Icelandic and Norwegian samples. Eight associate with ADHD; deletions at 2p16.3 (NRXN1), 15q11.2, 15q13.3 (BP4 & BP4.5–BP5) and 22q11.21, and duplications at 1q21.1 distal, 16p11.2 proximal, 16p13.11 and 22q11.21. Six of the CNVs have not been associated with ADHD before. As a group, the 19 CNVs associate with ADHD (OR = 2.43, P = 1.6 × 10−21), even when comorbid ASD and schizophrenia are excluded from the sample. These results highlight the pleiotropic effect of the neuropsychiatric CNVs and add evidence for ADHD, ASD and schizophrenia being related neurodevelopmental disorders rather than distinct entities.

Chromosomal microarray and whole-exome sequence analysis in Taiwanese patients with autism spectrum disorder.

BackgroundAutism spectrum disorder (ASD) is defined as a group of genetically and clinically heterogeneous neurodevelopmental disorders. Interplay between de novo and inherited rare variants has been suspected in the development of ASD.MethodsHere, we applied 750K oligonucleotide microarray analysis and whole‐exome sequencing (WES) to five trios from Taiwanese families with ASD.ResultsThe chromosomal microarray analysis revealed three representative known diagnostic copy number variants that contributed to the clinical presentation: the chromosome locations 2q13, 1q21.1q21.2, and 9q33.1. WES detected 22 rare variants in all trios, including four that were newly discovered, one of which is a de novo variant. Sequencing variants of JMJD1C, TCF12, BIRC6, and NHS have not been previously reported. A novel de novo variant was identified in NHS (p.I7T). Additionally, seven pathogenic variants, including SMPD1, FUT2, BCHE, MYBPC3, DUOX2, EYS, and FLG, were detected in four probands. One of the involved genes, SMPD1, had previously been reported to be mutated in patients with Parkinson's disease.ConclusionsThese findings suggest that de novo or inherited rare variants and copy number variants may be double or multiple hits of the probands that lead to ASD. WES could be useful in identifying possible causative ASD variants.